The puzzle of Hepatitis C Virus (HCV) is that it is recognized by the immune system, yet it causes persistent infections in roughly 85 percent of those exposed. We postulate that it is the quality of the immune response to HCV antigens that leads to chronicity rather than elimination of the virus. The quality and intensity of the immune response is determined by the cytokines elicited in response to HCV antigens and if the mediators produced upon exposure to virus do not favor eradication of intracellular pathogens, a state of chronic persistence may be established. We further postulate that the aggregate immune response to one or all of the HCV proteins may suppress appropriate helper T-cell responses that should lead to immune-mediated control of HCV infection. These studies are based on the premise that the peripheral blood may serve as a reservoir for continual re- infection of the liver, and thus an understanding of HCV immunobiology in the periphery is greatly needed. The aims of this proposal are: To assess and compare helper T-cell recognition of HCV antigens in patients who have anti-HCV antibodies, but with or without viremia; To characterize the quality of immune responses to HCV antigens as correlated with the cytokines produced; To identify the immunodominant epitopes of HCV antigens and to generate and characterize specific T-cell clones; To design and test protocols to foster appropriate anti-viral helper T-cell responses to HCV antigens. By understanding the underlying mechanisms of HCV persistence and the nature of the immune cytokines that are modulating host resistance, and by attempting to re-balance deficient responses through the use of supplemental cytokines, we may be able to identify additional avenues for therapy that, whether used alone or in concert with each other or vaccination, may enable us to control HCV infection and eliminate the major cause of chronic liver disease.